Cisplatin which is a platinum compound, and carboplatin which is an analogue of cisplatin, (which corresponds to a compound in which dichloride that is a leaving group of cisplatin is substituted with 1,1-cyclobutane dicarboxylate) have early been used in clinical practice as it is effective particularly for cancer of generative organs. On the other hand, a cisplatin substituted derivative (dichlorodiaminocyclohexane platin (hereinafter referred to as “dichloro DACH platin)) in which two amino groups (or two amino ligands), a leaving group of cisplatin, are substituted with diaminocyclohexne (hereinafter referred to as “DACH”), is known to have good anti-tumor activities and provides a stable complex. However, because such DACH platinum complex is substantially insoluble in water, derivatives obtained by substituting the chloride leaving group (or ligands) with various anionic ligands have been proposed for improving their solubility. Great interest has been taken in some of such derivatives because they have an activity on, for example, cisplatin-resistant L-1210 leukemia cells. In particular, oxalate substituting DACH platinum complex presents good water-solubility as well as has a high therapeutic index, and has been provided for clinical trial as a third-generation anti-tumor platinum compound (see non-patent literatures 1, 2 and 3 below).
On the other hand, a liposome complex is also proposed as another type of the derivatives above which is produced by a carboxylate substituting DACH platinum complex is synthesized with using two molecules of higher fatty acids for increasing its fat-solubility contrary to the oxalate complex and is stably enclosed in the liposome (see non-patent literature 4 below).
In particular, for the oxalate substituting DACH platinum complex above [also referred to as Pt(oxalato)-(dach)], as described in the left-hand column of page 1856 of the non-patent literature 1, trans- and cis-isomer have been isolated as a geometric isomer and, for trans isomer, trans-1 and trans-d isomer are also isolated as two trans-optical isomers. Of these, Pt(oxalato)-(trans-1-dach) or cis-[(1R2R)-1,2-cyclohexanediamine-N,N′]oxalato (2-)-O,O-platinum (II) (also referred to as oxaliplatin) has high water-solubility of 7.5 mg/mL (in 1.0M KCl aqueous solution at 37° C.). In addition, Pt(oxalato)-(dach) shows excellent ED90 in experimental animals bearing ascites sarcoma 180. In contrast with such oxaliplatin, Pt(malonato)-(dach), which has dicarboxylic acids the same as oxalate, but has a different ligand, malonate, which is formed by adding one methylene group between two carboxyl groups, has been reported to show about 5 times or more ED90 dose compared with Pt(oxalato)-(dach) (i.e. the drug efficacy shows one fifth or less) and half or less of therapeutic index of Pt(oxalato)-(cis-dach) (for example, see non-patent literature 5 below).
In addition to, so called low molecular prodrugs of Dichloro DACH platin as described above, high-molecular prodrugs using a polymer have been also proposed (see non-patent literature 6 below). In the non-patent literature 6, poly [N-2-hydroxypropyl]methacrylamide] (HPMA), poly(L-glutamic acid), poly(ethylene glycol)-block-poly(aspartic acid), oxidized dextran (OX-Dex) and the like are named as an example of polymers which can be used in such high-molecular prodrug systems, but only polymer complex of DACH platinum complex produced by using oxidized dextran or carboxymethyl-dextran (CM-Dex) is provided specifically. Furthermore, the non-patent literature 6 also describes that the OX-Dex complex has a more prolonged residual cytotoxic activity against experimental tumor cells in a serum-containing medium and shows stronger cytotoxicity compared with the CM-Dex complex. It is also suggested that such advantage of OX-Dex complex is due to the fact that DACH platinum complex will form a coordinate bond with OX-Dex stronger than with CM-Dex and steric hindrance level of the supporting polymer is also higher.